Dual resolution syringe

ABSTRACT

A syringe for accurately metering small volumes of fluid samples is provided with dual resolution capabilities. The syringe permits the aspiration of a tiny sample and also the dilution of a tiny sample with a much larger volume of reagent with the same syringe. The syringe also allows the aspiration of a minute fluid sample and the touchless transfer of the fluid sample from the tip of the syringe. The present invention allows the aspiration resolution to differ from the dispensing resolution. The dual resolution capabilities also permits the present invention to be implemented into existing conventional syringe drive system. The syringe may include a housing, a piston within the housing, and a plunger extending from the housing. A chamber is formed in the housing between the plunger and a sealing means and between the piston and the inner surface of the housing. The chamber may further include first and second portions, where the volume change of the fluid in the first and second portions corresponds to the dual resolution capabilities.

BACKGROUND OF INVENTION

[0001] 1. Field of Invention

[0002] The present invention relates to syringes which can accuratelymeter small volumes of fluid. In one embodiment, the syringe has dualresolution capabilities which enables the aspiration of a tiny sampleand also the dilution of the tiny sample with a much larger volume ofreagent (or another sample) with the same syringe.

[0003] 2. Discussion of Related Art

[0004] In recent years, diagnostic and analytic tests have requiredsmaller and smaller samples to be accurately metered, both to mix ordilute the samples with larger volumes of various reagents (sometimes inhigh dilution proportions) and to transfer them separately. There is ademand for samples less than 1 microliter and even less than 100nanoliters or even 10 nanoliters to be aspirated and delivered using asyringe or pipette system. Unfortunately, positive displacement devicesthat can accurately pick up the minute volume of the sample cannotprovide enough flow to completely transfer the sample and cannot alsometer large reagent volumes. Often times when transferring the sample,the sample will hang onto the tip of the syringe, which requirestouching the sample to another surface to free it from the capillaryaction and surface tension. A touchless transfer, where the sample isejected out of the syringe with enough force to prevent the sample fromhanging on the tip of the syringe, is desired. One way to increase theejection force of a syringe is to use a syringe with a larger diameter.Yet when the diameter of a syringe is increased to prevent the “hangingdrop” occurrence, the accuracy of the size of the sample aspirated iscompromised. While a larger diameter syringe can effect a touchlesstransfer, it cannot precisely aspirate a tiny sample, such as one asminute as 10 nanoliters.

[0005] Multiple pistons of different diameters contained within a singlepipette chamber or cylinder such as described below have been known inthe past. In such pipettes, spring means are used to keep the pistons inan upper position with a thumb-pressed button so that the pistons can bemoved against the force of helical springs to a pre-determined lowerposition. These systems have been used for a variety of purposes,including the transfer of small volumes of fluids.

[0006] In U.S. Pat. No. 5,383,372, assigned to DRD Diluter Corporation,a design is provided with a plurality of pistons that move together andseparately in a pipette chamber to measure a small sample and thendispense it with an air blowout to completely remove the sample. Whilethese systems have provided the capability of dispensing small sampleswith some significant air blow-off or touchless transfer, the demand forusing smaller and smaller samples require systems and devices whichpermit the aspiration and ejection of smaller and smaller samples. Theserequirements become more acute with the development of programs forgenetic testing of patient's blood and blood derivatives. Minuteaspirations of less than 100 nanoliters and often even 10 nanoliters arenow becoming important.

[0007] In many instances, it is desirable to deliver the samples by a“touchless” system that does not require the samples to be touched byanother surface, washed out by another liquid, or delivered beneath thesurface of another liquid. Therefore new delivery and syringe means arerequired. Satisfying these developing requirements has been difficultbecause drops tend to hang onto the tip of the delivery tube forming ahanging drop. The size of the hanging drops can vary widely, andsyringes or single piston devices with resolution fine enough to pick uptiny samples simply do not have the flow power to cleanly blow off thesample. A typical sample must be given a velocity when leaving the tipof the probe or pipette of at least approximately 1 meter per second tobreak free. The smaller the sample, the greater the inaccuracy caused bya hanging drop remaining on the syringe tip. For a variety of reasons,this escape velocity is particularly difficult to achieve with the verysmall syringes needed to handle very small samples. The problem isfurther complicated by the requirement that these transfer devices orpipettes be useful for materials that have a widely varied viscosity,from blood derivatives like serum to chemicals like DMSO to variousviscous genetic brews. The viscosity variation introduces furthervariations in the ability of a given sample to escape a confining tip.

[0008] Past efforts to achieve desired results involve theminiaturization of syringes to meter smaller and smaller samples.However, small syringes lack the flow power necessary to expel tinysamples. Smaller and smaller probe and pipette tips were developed sothat the lower flow rates and pressures the small syringes were able todeliver were artificially increased in an effort to achieve a tip escapevelocity. Tips with internal diameters as small as 0.010 inches weredeveloped and in recent years solenoid valve approaches have relied onsapphire drill channels as small as 0.002 inches to provide a sufficientvelocity lift at the tip. These delivery tubes result in very longnarrow columns of liquid passing through the syringe orifice, whichexposes a significantly large proportion of the total fluid volume todamaging surfaces. As a result, genetically related assays which helpedtrigger the interest in smaller pipettes are compromised because thesamples are damaged by the extensive surface area contact to which theassay material is subjected. Therefore, to prevent extensive surfacearea contact damage to the sample, it is beneficial to not use anexcessively small probe tip.

[0009] The demand for means and methods for metering very small volumesof material with significant resolution is increasing the need for pumpsand pipettes having the equivalent of 10 microliters syringe resolutionpower, with 1 microliters syringe resolution likely required in thefuture. These precise requirements for accurate dispensation of verysmall quantities of material present additional problems. For example,glass is a choice material because much diagnostic work benefits fromclear glass for visual inspection. In addition, glass is chemically veryinert. However, manufacturing glass tubes with very small internaldiameters precise and accurate enough to achieve the equivalent of a 10microliters traditional syringe is costly due to the small dimensions.Due to the rugged manufacturable larger sized components of the presentinvention, the prior problems associated with manufacturing tinysyringes is obviated.

[0010] Furthermore, traditional syringes for metering small and minutevolumes of fluid are troubled with sealing problems. Teflon seals arethe industry standard due to its low coefficient of friction and Teflonis chemically inert. However, Teflon has the undesirable characteristicof a high coefficient of thermal expansion and its size can varyconsiderably with temperature. These slight changes in properties arenegligible with a large syringe, but are physically noticeable withtraditional syringes that can handles small volumes of fluid. At roomtemperature, a Teflon seal fit for the internal diameter of a glasssyringe can slide smoothly within the housing and seal inside. Howeverat cooler or warmer temperatures, the Teflon seal can be too loose ortoo tight and “stick” therefore the piston cannot be moved as smoothlywithin the housing or the seal leaks. Since the present invention isable to achieve the resolution of a small syringe with largercomponents, thermal variations of the sealing material are enormouslyreduced with the present invention.

[0011] Additional concerns not only center on the need to meter smallerand smaller samples with finer resolution, but also there is anincreasing need for a more efficient method and means for delivering theselected sample in its entirety without damaging it. As noted, systemsused heretofore commonly attempt to solve this problem by adoptingprobes and tips with artificially small diameters intended to increasethe tip velocity of the material being delivered. These efforts haveresulted in mechanisms that have a ratio far in excess of 10:1 betweenthe length of the sample streaming through the tip and the diameter ofthe sample, which means greater exposure of the material being deliveredto surface contact. Applicant has found that if the height to diameterratio of the sample in a probe or pipette tip is not greater than 10:1the sample is likely relatively undamaged due to surface area contact.Furthermore, Applicant found that approximately 1:1 to 10:1 may beoptimal for blowing or blasting off discrete samples cleanly withoutdamaging them. Applicant has found for a sample as small as 20nanoliters (0.02 microliters), for example, a probe that is 0.011 to0.012 inches in internal diameter will support a stable slug of liquidwith a healthy height to diameter ratio of 1:1 whereas a solenoid drivensapphire probe ID of 0.003 inches would require a column 80 times astall as it is across. For samples in the 100 nanoliters-1 microlitersrange, a probe diameter of 0.016 to 0.022 inches is healthy anddesirable to keep the sample height to diameter ratio roughly in the 1:1to 10:1 range, but blowing off such a sample through such a healthydiameter probe with conventional techniques would require a syringe orplunger or piston much larger than could accurately meter or aspiratethe sample.

[0012] Traditional single piston syringes used for aspirating minutesamples are difficult to prime and keep clear of trapped bubbles. Due tothe small volume of the fluid sample, a few tiny air bubbles in thechamber can cause a high percentage of measurement error. Furthermore,the tiny outwardly pressing wiper seals of traditional small syringeswear out quickly. Efforts to get around these seal problems have led tousing o-rings and compression seals through which a piston slides,however problems have arose due to the sizes involved. For example, atraditional single piston 100 microliters syringe has an inside diameterof only 0.057 inches (1.4 mm) and a 10 microliters syringe has an ID ofonly 0.018 inches (0.46 mm). Therefore, it is essentially like trying toseal a needle. The above mentioned sealing and bubble entrapmentproblems have led to development of non-positive displacement techniquessuch as piezoelectric technology and solenoids, but these tend to beexpensive or require frequent timing-related calibration or are prone toclogging.

[0013] Further, the tiny ID of such small glass syringes are difficultto manufacture. The accuracy of measurement using a syringe is only asaccurate as the tolerances involved with manufacturing. The presentinvention succeeds in addressing this problem by grinding or lapping theouter diameters of the piston rather than trying to control the insidediameter of the tubing. When the tubing is glass it is typically formedover mandrels. The best commercial glass tubing production technique fora 1 milliliter syringe cannot control the inside diameter better than+/−0.0005 inches, or in extreme special cases down to +/−0.0002 inches.However, using precise outer diameter grinding techniques, the presentinvention can control the OD to more than an order of magnitude greater.The Applicant has found that this precise grinding of the outer diameterof the piston can be done to match the measured ID of lots of glasstubing to produce a differential resolution as fine as a 1-10 microliterconventional syringe. For example, if one needed resolution as fine as a10 microliters syringe, such as to aspirate 25 nanoliters, theconventional single piston syringe ID would need to be 0.01814 inches.This small size may be impractical for automated use. With the presentinvention, the same resolution may be accomplished with a glass tubewith a practical sized ID of 0.1814 inches and a piston with an OD of0.1804 inches. Without sacrificing resolution capabilities, the presentinvention includes practical sizes to work with and to manufacture.

[0014] Continuing with the above example, if the inside diameter of amanufactured lot of glass tubing was actually 0.1811 inches (rather thanthe intended 0.1814 inches) due to manufacturing variance, if undetectedthis could result in errors up to 20% in a dual resolution syringe.However, with the present invention, one can compensate for the variedID of the glass tubing lots by adjusting the grinding amount of theoutside diameter of the piston. Grinding the OD of the piston to 0.1802inches (rather than 0.1804 inches) will easily compensate for inherentvariations in the manufacturing process of the glass. As explained inmore detail below, because the present invention may use the differencein the cross-sectional areas between the glass chamber and the piston itnot only permits practical minute volume resolution but it can alsocompensate for the sometimes relatively crude manufacturing tolerancesof glass tubes.

SUMMARY OF INVENTION

[0015] The present invention overcomes prior limitations of conventionalsyringes that cannot accurately meter small volumes of fluid and/or thatdo not have dual resolution capabilities. Another feature of the dualresolution capabilities provided by the present invention is the abilityto facilitate a touchless transfer of a fluid sample from the tip of thesyringe. Furthermore, this invention permits positive displacement fluidmetering technology to handle small samples along the order of magnitudeof microliters (thousands of a milliliter) and even nanoliters(thousands of a microliter). The dual resolution feature also permitsthe aspiration resolution to differ from the dispensing resolution.

[0016] In one illustrative embodiment of the invention, a syringe isprovided with dual resolution capabilities. The syringe comprises ahousing with a chamber formed therein with a plunger and a pistonmovable within the housing. The volume of the chamber may vary bymovement of the piston or plunger or housing. The chamber may further bedefined by a first and a second portion of the chamber wherein thevolumes of each portion may change independently of one another.

[0017] A method of transferring minute quantities of fluid is alsoprovided, and in another embodiment a method of transferring multiplefluid samples from a single aspirated sample is provided.

[0018] In another illustrative embodiment, a syringe is providedoperating only under differential capabilities. The invention alsoincludes a device that is capable of diluting a minute sample with anexternal or internal reagent. Furthermore, the present inventionprovides a method for metering fluid samples where the aspirationresolution differs from the dispensing resolution.

[0019] The present invention helps to overcome the existing problemswith the prior art. The dual resolution syringe provides two modes wheresubstantially different volumes of fluid can be metered. Throughexperimentation, it was found that a large Bulk Mode flow capacity likethat of a 1 milliliter syringe in conjunction with a very fineDifferential Mode resolution like that of a 10-100 microliters syringeis able to transfer 0.05-1 microliters liquid aliquot and thentouchlessly transferring the liquid aliquot by utilizing an interposedair gap. This air gap is designed to be large enough to dispense thesample out of the syringe while in Bulk Mode. The dual resolutionsyringe picks up a tiny sample of approximately 1 microliters in theDifferential Mode and then uses the Bulk Mode to touchlessly transferthe sample by ejecting the sample out of the syringe along with most ofthe preceding relatively large 10-15 microliters air gap. Or the dualresolution syringe picks up a minute 0.05 microliters (50 nanoliters)sample and similarly ejects it with most of a preceding relatively huge2-4 microliters air gap. With the dual resolution syringe, theinterposed air gap can be perhaps 1-15 microliters with an aspiratedsample volume of 10 nanoliters to 1 microliters. In the presentinvention, the syringe size utilized in most of the examples provides adifference in the resolution of the two modes of operation of a factorof approximately 100, which was found desirable in experiments.

[0020] The present invention also facilitates high ratio dilution by theaccurate aspiration of a minute sample combined with the aspiration orinternal metering of a relatively large volume of a dilution fluid allby the same device. The volume of the dilution fluid will typically beat least 10 times greater than the volume of the sample. Prior artsyringes that could meter the volume required by the size of thedilution fluid are not able to aspirate a minute sample with precisionand accuracy. The dual resolution capability of the present inventionenables the accurate aspiration and combination of widely differentvolumes of sample and diluent.

[0021] Furthermore, the present invention permits positive displacementfluid handling technology to be used in conjunction with samples in themicroliter and nanoliter scale. “Positive displacement” simply meansthat a space-occupying mass or positive displacement element, such as apiston, enters a fluid-filled space and displaces that fluid from thespace in a volume equal to that of the positive displacement elementthat enters the space. Typical positive displacement syringes arelimited in measuring smaller and smaller samples due to manufacturingtolerances, seal performance, and general size constraints. In oneembodiment, the present invention utilizes the Differential Mode tosuccessfully meter samples as small as 10 nanoliters, illustratingpositive displacement fluid handling technology unhampered by previoussize limitations associated with conventional syringes that do notexhibit differential capabilities.

[0022] Further the present invention is designed to readily beretrofitted into an existing conventional syringe drive system andmodule. Previous dual resolution designs, such as the previouslydiscussed '372 patent, attempts required a completely new system ofsupporting hardware. The design of the present invention enables it tobe configured and sized similar to conventional syringes and may bereadily adaptable to and generally used directly in conventional singlepiston drive systems. This provides one with the ability to upgradeeasily to a dual resolution syringe. There is a vast array of prior artconventional single piston syringes equipped with a drive system andmodule. With the present invention, one can take out the conventionalsyringe and replace it with the present invention and have a dualresolution syringe system because the present invention is compatiblewith the existing supporting hardware for conventional syringes.Additionally, the present invention is applicable to both reusable anddisposable syringes.

BRIEF DESCRIPTION OF DRAWINGS

[0023] The accompanying drawings, are not intended to be drawn to scale.In the drawings, each identical or nearly identical component that isillustrated in various figures is represented by a like numeral. Forpurposes of clarity, not every component may be labeled in everydrawing. In the drawings:

[0024]FIGS. 1A and 1B illustrate the syringe in two selected positionsin detail;

[0025]FIG. 2 illustrates a detailed view of the bracketed range in FIG.1B;

[0026]FIG. 3 illustrates a tapered piston;

[0027]FIGS. 4A-4C illustrate one embodiment of the syringe that operatesin a Differential Mode;

[0028]FIG. 5 illustrates a syringe with associated surrounding equipmentin one embodiment;

[0029]FIGS. 6.1-6.5 illustrate the aspiration process;

[0030]FIGS. 7.1-7.5 illustrate the dispensing process;

[0031]FIG. 8A illustrates escape velocity data for conventional singlepiston syringes;

[0032]FIG. 8B illustrates column height and ballistic stability ratiosfor conventional single piston syringes;

[0033]FIG. 8C illustrates the “blastoff” process;

[0034]FIG. 9.1-9.6 illustrates the application of diluting a sample withan internal diluent;

[0035]FIG. 10.1-10.8 illustrates the application of diluting a samplewith an external diluent;

[0036]FIG. 11.1-11.6 illustrates the process of fluid sample pickup andtouchless “blastoff” Transfer;

[0037]FIG. 12.1-12.9 illustrates repetitive touchless “blastoff”transfer from a single aspirated sample;

[0038]FIG. 13 illustrates a further alternative embodiment; and

[0039]FIG. 14 illustrates a further alternative embodiment.

DETAILED DESCRIPTION

[0040] This invention is not limited in its application to the detailsof construction and the arrangement of components set forth in thefollowing description or illustrated in the drawings. The invention iscapable of other embodiments and of being practiced or of being carriedout in various ways. Also, the phraseology and terminology used hereinis for the purpose of description and should not be regarded aslimiting. The use of “including,” “comprising,” or “having,”“containing”, “involving”, and variations thereof herein, is meant toencompass the items listed thereafter and equivalents thereof as well asadditional items.

[0041] The dual resolution syringe 10 of the present invention is shownin FIGS. 1A-1B which illustrate the syringe in two selected positions,the functions of which will be described in detail in connection withthe other figures. The syringe 10 comprises a plunger 20, a housing 60concentric with and movable relative to the plunger, and a piston 40movable in and relative to the housing. The housing 60 defines a fluidreceiving chamber 30 at one end of the housing. As seen by comparingFIG. 1A and 1B, the volume of the chamber 30 is variable, controlled bythe relative position of the housing 60 and the piston 40. The piston 40is sized and shaped to occupy selected volumes of the chamber 30 and hasan outer surface 64 of the piston that is at least in part spaced fromthe inner surface 66 of the housing. The piston 40, thus has an end witha contiguous outer surface 64 spaced from the inner surface 66 of thehousing, in part defining the volume of the chamber. The outer surface64 of the piston is preferably uniformly spaced from the inner surface66 of the housing to form a portion 70 of the chamber 30. This annularportion 70 thus defines an annular chamber between the outer surface ofthe piston 64 and the inner surface 66 of the housing. Other shapedsegments, however, are contemplated. This may be achieved by shaping theouter surface 64 other than cylindrical. A second portion 72 of thechamber 30 includes the portion between the plunger 20 and the adjacentend of the piston 40. In one embodiment, the maximum volume of the firstportion 70 of the chamber 30 is significantly less than the maximumvolume of the second portion 72 of the chamber 30. A multiplying factorbetween the cross-sectional areas of the two portions 70, 72 ofapproximately 100 is preferred.

[0042] The syringe further includes a sealing means 24 which defines anend of the chamber at the end of portion 70. In one embodiment, thesealing means is a compression seal 24 fixed to the inner surface 66 ofthe housing and is axially movable with the housing relative to thepiston 40. In one embodiment, the compression seal 24 is a canted coilspring seal, although other compression seals may be used. Movement ofthe piston 40 toward the plunger 20 reduces the volume of the chamber 30by a volume equal to the volume of the piston 40 that moves through thecompression seal 24. Conversely, movement of the piston 40 away from theplunger 20 increases the volume of the chamber 30 equal to the volume ofthe piston moved in the opposite direction through the compression seal24. In one embodiment, movement of the housing 60 and sealing means 24relative to the piston 40 changes the volume of the first portion 70 ofthe chamber and movement of the piston 40 relative to the plunger 20changes the volume in the second portion 72 of the chamber.

[0043] The volume of the chamber 30 may be varied by movement of thehousing 60. From FIG. 1A to 1B, the housing 60 and the piston 40 movedown away from the plunger 20 and the volume of the chamber 30 isincreased. In one embodiment, the volume of the chamber 30 can be variedby either movement of the housing 60 relative to the plunger 20,movement of the piston 40 relative to the plunger 20, or cooperativemovement of both the housing 60 and the piston 40 with respect to theplunger 20.

[0044] The syringe further comprises a second sealing means 28 for thechamber 30. This wiper seal 28 is located on the end of the plunger 20adjacent to the chamber 30. The wiper seal 28 is fixed to the plunger 20and provides a sealing means between the plunger and the inner surface66 of the housing and also functions in part as the other defining endof the chamber 30. Located in the middle of the wiper seal 28 is anaxial hole 15 providing an exit and entrance for fluid entering thechamber 30 that is contiguous and continuous with an elongated passage22 extending through the plunger 20. Fluid flows in and out of thechamber 30 through the passage 22. As the volume of the chamber 30expands and contracts, the fluid in the passage 22 either moves into thechamber 30 or moves out through the passage 22. Additionally, the piston40 is sized to only move a portion of the fluid in the chamber 30 intothe elongated passage 22 extending through the plunger 20. Further, thesealing means 24 and the piston 40 are positioned within the housing 60to move a portion of the fluid in the chamber 30 into the elongatedpassage 22 extending through the plunger 20.

[0045] In an alternative embodiment, shown in FIG. 2, the wiper seal 28is cone-shaped with a channel running therethrough to axial hole 15,positioned with the larger end proximate the chamber 30 and the smallerend proximate the plunger 20. This shape helps to catch any rising airbubbles and sweeps the air bubbles that are clinging to the wall inwardand upward in the cone-shaped seal through the channel and out of thesyringe. Small air bubbles within the chamber can lead to measurementinaccuracy in the chamber. The above described embodiment helps toeliminate this problem.

[0046]FIGS. 1A-1B show a detailed view of the syringe 10. The housing 60may comprise a glass annular section 62 and a continuous metal annularsection 44. In alternative embodiments, the metal housing may betelescoping, and the exact placement of the glass and the metal mayvary. One benefit of the glass section 62 is to maintain optimalvisibility of the portion of the piston within the chamber and the wiperseal. It is understood that any type of transparent material, such asglass or plastic, would be beneficial to maintain optimal visibility ofthe portion of the piston within the chamber.

[0047] Attached to the metal section 44 of the housing is a cylindricaltube or bushing 68, preferably made of a low friction plastic of theacetyl family and is fixed to the metal section 44 intermediate the endsof the section, such as by press-fitting it into the metal section. Thelower end of the bushing 68 defines a ledge 46 which provides a stop fortab stop 48. Tab stop 48 comprises an annular flange fixed to andextending from the lower end of the piston 40. Tab stop 48 is describedat greater length below. A housing seal 26, such as an O-ring may belocated between the housing 60 and the bushing 68 to provide a sealbetween the glass housing 62 and the metal housing 44, or the housingseal 26 may be achieved with epoxy or other bonding material without theuse of an O-ring.

[0048] The syringe as shown in FIGS. 1A and 1B may be used inconjunction with an ancillary system for successive single aspirationsand ejections or multiple sequential aspirations and ejections.

[0049] In the embodiment of FIG. 5 which shows a typical hookup for asyringe, a tubular member 50, adjacent the plunger 20, is connected tothe top outlet of the plunger 20. The tubular member 50 retains fluidselectively in fluid communication with the fluid contained in thechamber 30 and the passage 22 extending through the plunger 20. Thechamber 30 volume decreases by fluid moving out of the chamber 50, intothe passage 22, and then further into other portions of the tubularmember 50, depending on the position of a chamber valve 32, hereafterdescribed. Likewise, the chamber volume increases by fluid in thetubular member entering the passage 22 extending through the plunger andfilling the chamber 30.

[0050] At the connection between the tubular member 50 and the plunger20 is a chamber valve 32. The chamber valve 32 controls the direction offluid flow out of the passage and the source of fluid into passage 22.The chamber valve 32 defines a storage container 34 side and a probe 36side of the tubular member 50. The operation of this valve 32 is bestillustrated in FIGS. 6.1-6.5 and FIG. 11 which also illustrate the basicaspiration process described in greater detail below. In FIG. 5, thechamber valve 32 is illustrated in position for fluid communicationbetween the syringe 10 and the probe 36 side. This position is primarilyfor aspiration and transferring of samples. Other figures, such as FIG.11.4 show the chamber valve 32 positioned for fluid communicationbetween the syringe 10 and the storage container 34 side. This positionis for initially priming the syringe and for increasing the volume offluid in the chamber 30, hereafter described in detail. When priming thesyringe, the tubular member 50 is filled with the fluid continuous withthe fluid in the storage container 34. Additionally, the priming stepmay include moving a portion of the fluid in the tubular member into thechamber 30.

[0051] The piston 40 is moved within the housing 60 by forces generatedby a resilient upward urging means, such as a helical spring 42, workingwithin the boundaries set by the housing cap 122 and the bushing ledge46 as shown in FIG. 1A and 1B. In one embodiment, the piston 40 definesan elongated internal space 58 within which a portion of the spring 42extends and engages the upper end of the internal space 58. Theelongated space 58 extends from one end of the piston to a point shortof the other end of the piston. The helical spring 42 is positioned toextend into the elongated space with one end of the spring engaging andbearing against the end of the elongated space 58 within the piston,while the other end of the spring engages a housing cap 122 which issecured at the end of the housing remote from the plunger 22. Thehousing cap 122 is secured to the metal section 44 of the housing. Themovement of the piston 40 into the chamber is limited by the tab stop 48located on the piston or by the fixed plunger wiper seal 28. As thepiston moves towards the plunger, the tab stop 48 prevents furthermovement of the piston as it contacts the ledge 46 on the bushing 68.The spring may always be loaded to keep the piston in position byitself. Other means for moving the piston can also be used, such as bypressurized air or fluid, by gravity, or by other types of linearactuators.

[0052] In one embodiment, the syringe is used for selectively dispensingfrom a chamber, a first and second volume of fluid having differentvolumes respectively, in the order of magnitude of at least 3 to 1. Thesyringe includes a housing which defines at least in part the chamber,and a piston positioned within the housing, defining a volume less thanthe volume of a coextensive length of the chamber.

[0053] In the embodiment of FIGS. 1A-1B, the housing cap 122 has a tap120 which is fitted for connection to a motor or actuator (not shown)and is removably attached to the housing 60. In one embodiment, themovement of the housing 60 is automated. The housing 60 may be moved byany form of a motor or actuator. While the housing cap 122 is removablyattached to the tap 120 by the use of a threaded connection, any form ofconnection, permanent or removable would be included in the scope of theinvention. The housing cap 122 closing the end of the housing remotefrom the plunger, further includes a housing cap post 124 fixed to thehousing cap which keeps the spring 42 axially aligned. The housing cappost 124 extending coaxially with the helical spring provides lateralstability to the spring 42 as it compresses and expands.

[0054] The syringe of this invention provides aspiration shown in FIGS.6.1-6.5 and ejection or dispensing, shown in FIGS. 7.1-7.5 of fluids intwo resolutions. Bulk Mode is defined as a coarse (low) resolution/highflow/high volume mode of the dual resolution syringe. In the Bulk Mode,the housing and the piston move together, causing the volume in thechamber to change. In Bulk Mode, the volume is displaced due to a changein the volume of the second portion 72 of the chamber. The volumedisplaced is equal to the cross-sectional area of the housing multipliedby the vertical displacement of the piston. If the housing iscylindrical and the radius of the inner surface of the housing is “R1”and the vertical displacement of the housing and the piston is “X”, thenthe volume displaced is equal to π(R1)² X. This is how volumedisplacement in a conventional single piston positive displacementsyringe is calculated.

[0055] Differential Mode is defined as a fine (high) resolution/lowflow/low volume mode of the Dual resolution syringe. In the DifferentialMode either the housing moves relative to the piston, or the pistonmoves relative to the housing. In Differential Mode one of either thepiston or the housing is stationary. As previously stated, the outersurface 64 of the piston is preferably uniformly spaced from the innersurface 66 of the housing to form a first portion 70 of the chamber 30.In Differential Mode, the volume displaced is equal to the volume changein the first portion 70 of the chamber. This volume change is equal tothe difference in the cross sectional area of the housing and the pistonmultiplied by the vertical displacement of either the piston or housingrelative to one another. If the piston is cylindrical and the radius ofthe piston is “R2”, then the displaced volume is equal to[π(R1)²−π(R2)²]X.

[0056] Bulk and Differential Mode provide many advantages in the presentinvention. For example, when in Bulk Mode, the syringe is capable ofmetering a large volume of fluid very quickly and within a high flowrate. Then, in Differential Mode, the syringe is capable of metering avery precise and accurate small volume of fluid very smoothly. Since thesyringe is capable of switching back and forth between Bulk Mode andDifferential Mode, a wide range of precision and flow rate/volume isobtained with the syringe of the present invention. Alternatively, Bulkand Differential Mode may be used to provide an aspiration resolutionthat differs from the dispensing resolution.

[0057]FIG. 6.1 represents a “home” or top position, at the start of theDifferential Mode. The top of the piston 40 is in contact with the wiperseal 28 and the spring is fully compressed. Previous to this position,the device had been primed by movement of the chamber valve 32 to permitfluid communication between the storage container 34 side and thesyringe 10. FIG. 6.2 illustrates downward movement of the housing 60relative to the piston 40. This operates the differential capabilitiesof the present invention, as the volume aspirated into the device isequal to the difference in cross-sectional areas between the piston andthe housing times the distance or height traveled. This DifferentialMode enables high precision and accuracy. FIG. 6.3 shows the transitionpoint between Differential Mode and Bulk Mode, because the ledge 46 onthe bushing contacts the tab stop 48 on the piston. At this stage, thespring 42 is minimally compressed. As the housing 60 continues to movein the downward direction, FIG. 6.4 shows a midpoint in Bulk Mode. Thepiston 40 and the housing 60 move together causing the volume of thechamber 30 to increase in the second portion 72 of the chamber. In BulkMode, the volume aspirated is relatively large and the device operatessimilar to a standard single piston syringe. FIG. 6.5 illustrates amaximum chamber 30 volume.

[0058]FIG. 7.1 shows the device at a bottom position, similar to FIG.6.5. In FIG. 7.2 the housing moves up in Bulk Mode, causing movement ofthe compression seal 24 against the inner surface 66 of the housing,displacing a volume of the second portion of the chamber. FIG. 7.3 showsthe transition point between Differential Mode and Bulk Mode where thepiston 40 contacts the wiper seal 28 while FIG. 7.4 illustrates amidpoint in Differential Mode. By FIG. 7.4, the fluid in the chamber 30has generally traveled through the elongated passage 22 and isapproaching the probe tip 38 for dispensing. FIG. 7.5 shows the deviceback to the “home” or top position, with the system primed and ready fordispensing.

[0059] The combination of Bulk Mode and Differential Mode in the syringeof the present invention enables this device to accurately and preciselypick up a minute sample (in Differential Mode) and then blow it offtouchlessly with a high velocity (Bulk Mode) via a sufficiently largesafe air buffer zone to provide touchless transfer, as shown and laterdescribed in FIG. 8C. This entire process of accurately picking up aminute sample and completely transferring it is shown in FIG. 11.

[0060]FIG. 8A shows the limitations of the prior art conventional singlepiston syringes. A tip velocity greater than 1 meter/second shouldprevent a “hanging drop” on the probe tip for most samples. Largerdiameter syringes, such as a 1 milliliter syringe with a 0.181″ insidediameter can impart enough flow rate to a sample to give a tip velocityover 1 meter/second using a probe tip with a diameter as large as0.020″. The resolution for a syringe of this size is 0.06 mm/microliteror 424 microliters/inch. This equates to a maximum flow of 424microliter/second, using a fast automated instrument speed of 1″/second.With a traditional whole step stepper motor drive with 2000 steps over afull syringe length of 6 cm (2.37″), the resolution converts into 0.5microliter/step (500 nanoliters/step). It is generally accepted, andalso described in further detail below, that with a 1000 microlitervolume syringe, the smallest volume sample one can aspirate and stillachieve consistent precision and accuracy better than 1% is 100microliter. If a smaller sample volume is needed with the same precisionand accuracy, then a conventional single piston syringe with a smallerinside diameter is used. However, as shown in FIG. 8A, while theresolution of a syringe is higher with a smaller volume/smaller diametersyringe, the occurrence for a hanging drop increases using a smallersized syringe, because a sufficient tip escape velocity cannot bereached.

[0061] For example, if one needed to accurately pick up a 1 microlitersample with a conventional syringe, FIG. 8A shows that the syringe wouldneed to be as small as 10-100 microliters, and that for such a syringeto impart a tip escape velocity of greater than 1 meter/second to thatsample, the probe tip would need to be very tiny—approximately 0.002″ to0.005″. But FIG. 8B shows that such a necessary tiny diameter probe tipwould require that the length of the sample passing through that tipwould be 40 to 620 times as much as the diameter, a destructive ratio.FIG. 8B shows that a 0.020″ ID probe tip would give a healthy 10:1 ratiofor such a 1 microliter sample, and FIG. 8A shows that the 1 millilitervolume syringe size could easily impart the needed tip escape velocityfor such a proper sized tip. However, a conventional syringe whosedispensing resolution must equal its aspiration resolution cannotachieve both. The present invention overcomes these problems by allowingthe aspiration resolution to differ from the dispensing resolution.

[0062]FIG. 8B further illustrates the limitations associated with theprior art, showing ballistic stability ratios for different sizedsamples in probes of different diameters. The ballistic ratio is theheight to diameter ratio. The greater the ratio the greater theexcessive surface tension and surface contact which can cause geneticfragment damage or viscosity effects. A ballistic ratio of approximately1:1 to 10:1 is ideal to minimize the damage to the sample. However withconventional syringes, this ballistic ratio limits the resolution andthe touchless blowoff capabilities.

[0063]FIG. 8C shows the fundamental blastoff mechanism. FIG. 8C-1illustrates a side by side comparison of a 50 nanoliter sample #A, and a500 nanoliter sample #B, aspirated into a 0.012″ probe inside diameterand a 0.020″ probe respectively. FIG. 8C-2 shows a clean blastoff ofboth samples despite their small size. This is possible because whileboth samples are accurately aspirated in Differential Mode, they aredispensed in Bulk Mode. FIG. 8C-3 illustrates how the prior artsyringes, such as a conventional 10 microliter syringe, are capable ofaspirating the small samples but fail to blastoff the samples due totheir feeble flow rates. In 8C-3 ^(#)C there is schematicallyillustrated prior art single piston and chamber which is capable ofblast off but not capable of accurately aspirating small samples, while8C-3 ^(#)D shows a prior art single piston and chamber having a muchhigher ballistic stability ratio than 8C-3#C that is capable ofaspirating small samples accurately, but not capable of blastoff. FIG.8C-3^(#)E, illustrates how the prior art would dispense using FIG.8C-3^(#)D.

[0064] In addition to the aspirating diversity, dual resolution makesthe syringe capable of the dilution of small samples with large volumesof diluent using only one syringe. The present invention enablesdilution to occur using an internal source for the reagent as shown inFIG. 9.1-9.6. In this particular embodiment, a 0.1 microliter sample isdiluted with a 300 microliter diluent in a syringe with a 0.012″ IDprobe tip. This provides a 3000:1 dilution ratio. In this particularembodiment, the syringe has capabilities of holding 3.5 microliters inthe first portion 70 of the chamber, and 300 microliters in the secondportion 72 of the chamber. In FIG. 9.1, the syringe starts out in homeposition with the probe primed all the way to the tip 38. FIG. 9.2illustrates the aspiration of 3 microliters of air. In this embodiment,a stepper motor (not shown) driving the system moves 600 steps toaspirate this quantity in Differential Mode. In FIG. 9.3 the sample isbrought to the probe tip 38 and aspirated in Differential Mode bymovement the stepper motor. FIG. 9.4 shows the valve changing to thestorage container 34 side and then the syringe 10 moves down in BulkMode to increase the volume of the chamber 30. To eliminate backlash,the housing then moves up a small amount. Then the chamber valve 32changes back to the probe 36 side. FIG. 9.6 shows the dispensing of the0.1 microliter sample along with 300 microliters of the diluent, whichin this example is the internal priming fluid. To dispense the fluid,the syringe 10 moves in Bulk Mode. The tiny sample that was accuratelyaspirated is ejected from the syringe with a controlled amount of aninternal reagent. This may be done at a very high velocity to achieveeven mixing.

[0065] The invention also enables dilution using an external source forthe reagent as illustrated in FIG. 10.1-10.8. A tiny sample 200 isaspirated in Differential Mode and a larger dilution fluid 201 isaspirated in Bulk Mode. Both the sample and the diluent are then ejectedfrom the syringe for mixing in container 203. Most conventional syringesare not capable of diluting a small sample using one syringe because thesyringe is not capable of accurately metering such a wide range ofvolumes of fluid. However, Bulk Mode in conjunction with DifferentialMode makes dilution with one syringe possible. Typically, the volumetricdifference between Bulk Mode and Differential Mode is at least 3:1.

[0066]FIGS. 10.1 to 10.8 shows a syringe similar to the one in FIG. 9where the syringe has capabilities of holding 3.5 microliter in thefirst portion 70 of the chamber 30, and 300 microliter in the secondportion 72 of the chamber. In FIG. 10.1 the syringe is shown completelyprimed with the storage container solution 204. In FIG. 10.2, 10microliters of air is aspirated by movement of the housing 60 and inFIG. 10.3, a 300 microliter external reagent or diluent 201 is aspiratedin through the probe tip 38. In FIG. 10.4, the chamber valve 32 changesand the housing 60 moves up to empty some of the priming fluid in thechamber 30 to the storage container 34 side. Another volume of air 206is aspirated in FIG. 10.5, and in FIG. 10.6, a 100 nanoliters sample 200is aspirated. This second volume of air separates the diluent 201 fromthe fluid sample 200. In preparation for dispensing the diluent and thesample, FIG. 10.7 shows the syringe repositioning back to Bulk Mode bymovement of the chamber valve 32 to the storage container 34 side andmovement of the housing 60 all the way down filling the chamber 30. Oncerepositioned, FIG. 10.8 shows the valve switching back to the probe 36side to dispense the approximately 308 microliters, comprising the 100nanoliters sample, the 3 microliters volume of air, the 300 microlitersdiluent, and approximately half of the first volume of air. Dispensing aportion of the air volume between the diluent 201 and the priming fluid204 assures that the full amount of the diluent is dispensed, withoutthe risk of intermixing with the priming fluid.

[0067] The above dilution examples show how a minute fluid sample and alarge fluid volume can be aspirated into the syringe of the presentinvention with precision and accuracy. Traditional syringes are capableof achieving approximately 1% precision and accuracy. The precision andaccuracy of an aspiration is determined by the volume aspirated incomparison to the total volume capable of being aspirated. For example,with a conventional single piston syringe a 10 microliter volume syringeis capable of achieving 1% precision and accuracy aspirating a 0.1microliter (10 nanoliters) sample. Furthermore, a conventional 1milliliter volume syringe is only capable of achieving 1% precision andaccuracy with a sample as small as 0.01 milliliters (1 microliter).However, the present invention enables a broader range of sample volumesto be aspirated with precision and accuracy of at least 1%. In aconventional single piston syringe, the maximum volume ratio one canachieve with at least 1% precision and accuracy is 100:1. However,because the present invention implements two modes, a volume ratiogreater than 100:1 and even greater than 3000:1 may be achieved with thesame precision and accuracy.

[0068] In one embodiment, the present invention consists of a devicethat can provide fluid aspiration as fine as that of a 10 microlitersvolume syringe (4.24 microliters/inch, inside diameter of 0.01814″)while at the same time, when driven at a speed of 1 inch per second, canprovide flow as fast as a 1 milliliter volume syringe (424microliters/inch, inside diameter of 0.01814″) to deliver a samplethrough even a large 0.20″ ID tube (#21 gage hypodermic needle) at avelocity of 1.8 meters per second.

[0069] In a further method of operation of the syringe 10 shown in FIG.11, a tiny or minute quantity of a fluid sample is transferred. Tiny isdefined as a small quantity in the order of magnitude of 1microliters—100 nanoliters. Minute is defined as a small quantity in theorder of magnitude of 10-100 nanoliters. The tubular member 50 isusually primed with a first fluid 220, which involves filling a portionof the tubular member 50 with the first fluid as shown in FIG. 11.1. Thetubular member is primed with the fluid 220 from the storage container34 to flush out any air or fluid from the tubular member and chamber 30.The priming step also includes filling the chamber 30 and the passage 22extending through the plunger with the first fluid 220. Then inpreparation for the aspiration of the sample, a portion of the tubularmember near the first end or probe tip 38 of the tubular member isdevoid of the first fluid 220. In the embodiment of FIG. 11.2, this isaccomplished by aspirating a quantity of air 221. This amount of air isdefined as an air gap or air buffer zone which facilitates the touchlesstransfer of the minute sample. Then, the probe tip 38 is introduced intoa reservoir 224 of the sample 225, as shown in FIG. 11.3. FIG. 11.4illustrates that once the sample 225 is aspirated, the chamber valve 32changes to provide fluid communication between the syringe 10 and thestorage container 34 side. In preparation for ejecting the sample, withthe syringe 10 open to the storage container 34 side, the housing 60moves farther down, repositioning to the Bulk Mode zone and increasesthe volume of the chamber 30 with fluid from the storage container 34side. Differential Mode may provide enough precision and accuracy forlarger volumes in which the error from the hanging drop may be small,but to blowout a tiny sample accurately without the significant (andoften variable) error of a hanging drop, Bulk Mode may be needed toprovide the necessary ejection or air blowout velocity. By firstswitching the chamber valve 32, the syringe is repositioned to Bulk Modewithout disturbing the aspirated sample on the probe 36 side. When therepositioning is completed, as shown in FIG. 11.5, the chamber valve 32switches back to provide fluid communication between the syringe 10 andthe probe 36 side. The exact position in the Bulk Mode zone does notmatter as long as it starts at a position that gives enough room to letthe syringe blowout the sample and the desired volume of air out and offof the probe tip 38, while still remaining in the Bulk Mode zone.

[0070] The fluid sample 225 is ejected from the first end 227 of thetubular member by movement of the first fluid 220 from the tubularmember. This forces a quantity of air positioned between the first fluidand the fluid sample from the tubular member, entraining the fluidsample 225, and positively moves it from the first end 227 by the forceof air movement as shown in FIG. 11.6. The volume of air 221 ejected issignificantly larger than the minute sample 225. The volume of air alongwith the probe tip 38 diameter permit the minute sample 225 to beejected intact from the probe tip 38 with the necessary high flow rateof Bulk Mode. The quantity of air 221 positioned between the primingfluid 220 and the fluid 225 sample imparts an air blowout velocitygreater than 1 meter per second.

[0071] Experimentation has shown that if the sample volume picked up was1 microliter with an 0.020″ inside diameter probe, then the desiredtotal air blow out volume may be 7 or 8 microliters out of a total 10-15microliters of air aspirated. If the sample volume picked up was 0.1microliters (100 nanoliters) or less with, for example a 0.012″ ID probethen the total air blow out volume may be 2 microliters out of a totalof 3-5 microliters of air aspirated. Preferably, the volume of the firstfluid aspirated is in the order of magnitude of 10 times the secondvolume of fluid. However, the first volume of fluid may be in the orderof magnitude of 100 times the second volume of fluid or even greater.

[0072] In a further method of the present invention, a fluid sample inthe order of magnitude of about 1 microliter or less is delivered byplacing the sample in a tubular member having an open end and an innerdiameter of in the order of 0.020″ or less, and thereafter impelling thesample through the open end under the influence of a fluid medium movingthrough the tubular member at a speed in excess of about one meter persecond.

[0073] A further embodiment of the invention shown in FIG. 12 enablesthe aspiration of a sample and subsequent sequential touchless ejectionsof multiple smaller discrete portions of the sample. As previouslydescribed and shown in FIG. 12.1-12.2, first the tubular member 50 isprimed and a volume of air 221 is aspirated up into the probe tip 38.The fluid sample is then brought into contact with the probe tip 38 toaspirate the desired volume of the sample 225 as shown in FIG. 12.3. Inone embodiment, the volume of the fluid sample aspirated is much largerthan the volume of the individual sample volume aliquots or portionsthat will be discretely ejected. For example, if a preferred individualsample volume is 500 nanoliters, then the total sample volume aspiratedmight be 10 times that amount.

[0074] A second volume of air 221 A is then aspirated through an airshunt 52 shown in FIG. 12.4. The air shunt 52 is an extension of theprobe 36 body that branches offending in an air shunt valve 54 which maybe a valve position shared with the chamber valve 32. The air shunt 52extends from the tubular member in fluid communication with the airshunt valve 54. When the air shunt valve 54 is opened, air enters theair shunt 52, bisecting the aspirated fluid sample 225 into two distinctvolumes. The air shunt 52 is positioned so that the volume of the fluidsample between the entrance of the air shunt into the probe body and theprobe tip 38 after the bisection is equal to the desired individualsample aliquot volume. Therefore the individual sample volume, orseparated aliquot 225A, is separated from the remaining fluid sample inthe tubular member 50 by the volume of air 221A aspirated through theair shunt valve 54. Once the individual sample volume of the desiredamount is positioned at the probe tip 38, the air shunt valve 54 isclosed.

[0075] In preparation for ejecting the individual sample, the chambervalve 32 is switched from the storage container 34 side to the probe 36side and the syringe is positioned to Bulk Mode for ejecting the sampleas shown in FIG. 12.5. Since the chamber valve 32 was switched toprovide fluid communication between the syringe 10 and the storagecontainer 34 side, the priming fluid entering the chamber 30 comes fromthe storage container 34. The chamber valve 32 switches back to open upto the probe 36 side opening up the passage 22 leading into the chamber30 to the probe 36 side. Remaining in Bulk Mode, the housing 60 moves uptowards the plunger 20 to eject the individual sample volume 225A out ofthe tubular member 50 at a high velocity by movement of the primingfluid toward the probe tip 38 shown in FIG. 12.6. In one embodiment, thehousing 60 moves up a distance calculated to dispense a volume of airequal to approximately 50-80% of the volume of air 221A bisecting thefluid sample 225 volume. For example, if 5 milliliters of air isaspirated through the air shunt valve 54, the housing 60 moves uptowards the plunger 20, a distance calculated for the ejection of about3 milliliters out of the probe tip 38. This volume ejected from thetubular member 50 does not have to be precise. The volume of airselected is intended to provide a non-precise ejection by the coarseBulk Mode to extend safely into the main body of the air buffer zone,while also expelling the much smaller sample aliquot 225A at the tip 38.This will completely blastoff the individual sample aliquot from the tip38 while still maintaining a separation between the remaining fluidsample in the tubular member 50 and the priming fluid in the tubularmember.

[0076] To set the system up for the next individual sample volumeejection, the remaining fluid sample in the tubular member 50 must berepositioned as shown in FIG. 12.7, to measure out the desired volume ofthe next individual sample volume aliquot. In one embodiment, the fluidsample is repositioned with an air detector 56 located on the tubularmember 50, located approximately where the air shunt 52 branches outfrom the probe 36. A conventional air detection system may be used,depending on the specific applications involved. One embodiment of thepresent invention employs an optical detector that senses the changebetween air and a fluid. However, other detection systems may be used.Using a detector, the fluid sample in the tubular member 50 is movedtoward the first end or probe tip 38 until the fluid sample is adjacentthe air shunt 52 as shown in FIG. 12.8. Then, the remaining fluid sampleis further moved toward the first end until the fluid sample is adjacentthe first end or probe tip 36 as shown in FIG. 12.9.

[0077] The Differential Mode of the dual resolution syringe is used toprecisely accomplish the repositioning of the fluid sample flush withthe probe tip 38. First the chamber valve switches to the storagecontainer side and the housing 60 and the compression seal 24 move upwith respect to the plunger 20, reaching the bottom of the DifferentialMode. The housing then moves slowly up in the Differential Mode, slowlyand smoothly pushing the remaining sample downward. In one embodiment,as soon as the air detector 56 detects the leading edge of the fluidsample the pump motor stops, thus stopping the movement of the housing60 and the compression seal 24 as shown in FIG. 12.8. Conventionalcircuitry may be used to control the pump operation in response to theair detector. In this step, it may be beneficial for the housing and thecompression seal to move slowly, smoothly and precisely to prevent anyof the fluid sample in the tubular member from seeping past orovershooting the air detector 56. This accurate movement of the dualresolution syringe could not be accomplished adequately in Bulk Mode, orwith any large single piston syringe. A microprocessor controls how farthe chamber must move to fill the volume between the air detector 56 andthe probe tip 38, and communicates with the motor to move the additionaldistance. This pushes the fluid sample in the tubular member 50 downuntil it is again flush with the probe tip 38 as in FIG. 12.9. Next,another individual sample volume aliquot or sample portion is separatedfrom the remaining portion of the fluid sample in the tubular member 50by bisecting it with a third quantity of air and then the sample isejected from the probe tip 38 as explained above. These steps arerepeated until the desired number of separate aliquots of sample havebeen dispensed.

[0078] In an alternative embodiment, the fluid sample in the tubularmember is repositioned down to the first end or probe tip 38 in one steprather than in two steps. In the one step process, an air detector 56 isnot required, but rather the fluid sample is moved down the tubularmember 50 by a distance that would approximately bring a portion of thesample to the level of the probe tip 38. However, the two step processmay be preferred because then the exact position of the fluid sample inthe tubular member is reset to a calibrated position in the first step,and the individual sample volume is measured out precisely andaccurately in the second step. Additionally, while in one embodiment,the system is automated with an air detector 56 connected to the pumpmotor, the scope of the invention encompasses many manual operations andsample positioning detecting schemes as well.

[0079] In an alternative embodiment shown in FIG. 3, a piston 140 istapered slightly with an outer diameter that decreases or increases overthe length of the piston. It is substituted for piston 40 in the otherembodiments herein described. This adds flexibility to the syringebecause one can alter the resolution in the Differential Mode. Forexample, a syringe of the present invention will have certain resolutioncapabilities with a piston that has an outer diameter of 0.1810 inches.If the inner diameter of the housing is constant, and the same syringeis used with a piston that has an outer diameter of 0.1806 inches, theresolution capabilities will change because the distance between theinner surface 66 of the housing and the outer surface 64 of the pistonincreased by 0.004 inches. With a tapered piston design, one can varythe resolution capabilities of the Differential Mode without needingmultiple pistons. To vary the resolution capability with a taperedpiston, the position of the piston is adjusted to the desired level. Aslong as the taper of the piston from one end to the other is deigned tobe small, there is not a need for a different sized seal. In oneembodiment, the taper is approximately between 0.001-0.004 inches. Thetaper could be outside of this range, however too large of a taper willcreate sealing problems between the outer diameter of the piston and thehousing. However, it is understood that this problem is alleviated withusing a flexible or compressible seal.

[0080] The present invention is designed for use for either reusablesyringes or disposable syringes. Typically the reusable marketincorporates a glass portion of the housing, while a disposable one-timeuse syringe employs a plastic portion of the housing and or plastictips. The present invention is not limited to a particular type ofmaterial or construction. Additionally, in the reusable syringe market,experience has shown that over time the seals and piston may wear outfrom use requiring replacement parts. The scope of this invention coversthe replacement parts associated with the present invention. Forexample, in one embodiment of the above described syringe assembly thatincludes an elongated housing with continuous sidewalls that define anoutlet end, the present invention includes a closure means for movablysealing the outlet end along the inner surface of the sidewall. Theclosure means selectively defines different volumes within said housingand also defines an opening there through extending to said outlet end.An example of this embodiment would cover a replacement plunger and inone embodiment, the replacement plunger includes a cone-shaped seal witha channel there through with the larger end of the seal proximate theoutlet end. As previously explained, this seal shape helps to catch anyrising air bubbles and sweeps the air bubbles that are clinging to thewalls inward and upward in the cone-shaped seal through the channel andout of the syringe.

[0081] In an alternative embodiment, illustrated in FIG. 13 dualresolution is accomplished with a syringe 110 for selectively dispensingfrom a chamber 116 a first or second volume of fluid having differentvolumes in the order of at least 3 to 1. This syringe 110 includes apiston 379 positioned within the housing 360, and the piston includes atleast two distinct segments, 112 and 114, the smaller of which may slidein and out of the larger segment via a seal 382. The first or largersegment 112 of the piston moves within the housing 360, varying thevolume of the chamber 116. Likewise, the second or smaller segment 114of the piston 379 moves within the housing, varying the volume of thechamber 116. The first and second segments of the piston 112, 114 caneither move independently of one another or together. In one embodiment,the housing is stationary and both the first and second segments 112,114 move relative the housing. In another embodiment, the housing ismovable relative to the piston. The first segment 112 of the piston hasa slightly larger cross-sectional area compared to the second segment ofthe piston. In one embodiment, the multiplying factor between thedifference between these two cross-sectional areas and the area ofeither segment alone is at least 3 and can easily be 100. Thisdifference in cross-sectional areas helps to facilitate the dualresolution capabilities of the syringe. Further if the housing alsomoves one may create a triple resolution syringe which may provideincreased precision. Movement of the first segment of the piston 112varies the volume of the chamber in the above described Bulk Mode, whilemovement of the second segment of the piston 114 varies the volume ofthe chamber in the above described Differential Mode. FIG. 13 shows theouter surface of the first segment of the piston separated from to theinner surface of the housing by sealing means 380. The second segment114 of the piston is encompassed within a recessed portion 362 in thefirst segment 112 and slides along seal 382 by spring 364. The means forselectively moving the first and second segments of the piston 112, 114to displace a second and first volume of fluid includes all previouslymentioned means in other embodiments of the present invention. Also, thescope of the invention includes other embodiments where the arrangementof the first and second segments of the piston within the housing isvaried. Furthermore, this alternative embodiment may include a notch 370in a piston segment to provide for fluid communication when the pistonsegment approach the passage 322. This embodiment may be described as atelescoping piston arrangement, or also a plunger within a piston. Theinvention also contemplates the use of pistons with more than twosegments.

[0082] The embodiment of FIG. 14 illustrates a telescopingpiston/plunger arrangement similar to FIG. 13 incorporated into astationary housing. This embodiment is advantageous because it enablesdual resolution capabilities using a glass housing and system of aconventional single piston syringe. Segments 114 and 112 move relativeto the stationary housing 360. Segment 114 is in a telescopingarrangement, capable of moving inside of segment 112. The volume of thechamber 116 is a function of the position of each segment 112 and 114.

[0083] All of the above described embodiments allow a volume of air tobe aspirated that is many times greater than the size of one minutesample. This volume of air, along with the probe tip diameter, permitsthe precise aspiration of a minute sample by the fine resolutionDifferential Mode of the syringe and its touchless intact ejection fromthe probe tip by the necessary high flow rate of the Bulk Mode.

[0084] In one embodiment, the single piston syringe of the presentinvention is provided with a dynamically sealed spring-driven pistonthat operates within a dynamically sealed motor-driven housing. Achamber within the housing is defined by two seals that permitadjustment of the chamber volume by movement of the piston and thehousing with respect to an immobile plunger. Two differentspace-occupying masses, the piston 40 and the housing 60, enable thesyringe to accurately and precisely meter minute volumes of fluid whilealso deploying relatively very large volumes and high powered flowvelocities. This range of accuracy and flow capacity provides a uniqueability to transfer minute liquid samples without the need to touch themoff.

[0085] In the alternative embodiment illustrated in FIGS. 4A-4C, thesyringe 200 only operates in Differential Mode. FIGS. 4A and 4B show howthe first portion 70 of the chamber remains in fluid communication withthe elongated passage extending through the plunger via a breakout hole208. From FIG. 4A to FIG. 4B, the housing 60 moving down increases thevolume in the chamber portion 70. In this embodiment, there is not aBulk Mode, but rather the device only operates using the differentialcapability. FIG. 4C shows one embodiment where the plunger 20 and thepiston 40 are formed into or from one piece, with the wiper seal 28 slidup over the assembly, fixed just above the breakout hole 208.

[0086] This embodiment shows how the present invention permits positivedisplacement fluid handling technology to meter samples in themicroliter and nanoliter scale. When the positive displacement element,such as a piston or the plunger, moves toward the outlet, the fluid ispushed outward. When the positive displacement element is withdrawn, itexerts a vacuum and pulls the fluid into the sampling device inward.Positive displacement devices are operated automatically or manually,and in general it is known that they are highly controllable and highlydeveloped, reliable and trusted. Typical syringes operate as a positivedisplacement device. One example is a syringe having a solid plungerwith a typical Teflon tip at the end of the plunger serving as anoutwardly-pressing seal when it slides against an inner surface of atube. Other variations use different sealing materials such aspolyethylene, and other rubber compounds, such as Buna, a syntheticrubber made from the polymerization of butadiene and sodium. Anothervariation of a positive displacement device includes a single pistonthat passes through a compression seal inside of a tube.

[0087] In the embodiment of FIG. 4, the housing forms a chamber definedby the inner surface of the housing 60 and spaced portions of the outersurface of the piston 40. In one embodiment, the cross-sectional shapeof the chamber is annular, however other configurations may be used.This embodiment includes means extending from an end of the pistondefining a passage for fluid to flow out of the chamber. In oneembodiment, shown in FIG. 4C, there are means extending from an endcomprising an extension of said piston having an axially extendingpassage with one end of the passage in fluid communication with thechamber and the other end of the passage extending outwardly of thechamber. Other means defining a passage for fluid flow may beunconnected to the piston. As described in other embodiments above, theembodiment of FIG. 4A-4C may further include sealing means fixed to theinner surface of the housing, movable relative to the piston or plunger,forming an end of the chamber. This embodiment may also include a secondsealing means fixed to the extension of the piston forming an end of thechamber. This embodiment is used for metering small and minute samplevolumes and is advantageous over conventional syringe designs becauseminute sample sizes can be accurately aspirated using larger components.Since the chamber size is defined as the volume in between the pistonand the housing, the sizes of the piston, housing, and sealing means arelarger relative to a conventional syringe with the same resolutioncapabilities. Additionally, this embodiment may be modified to include apiston that has a frusto-conic section forming a tapered section and atleast one resilient seal between the inner surface of the housing and aportion of the frusto-conic section.

[0088] As described above, the market for positive displacement devices,in particular in the medical and biomedical fields, has demanded finerand finer resolution with better precision and accuracy in meteringsmaller and smaller samples. This has led to positive displacementdevices with smaller inner diameters. However, when manufacturingsmaller and smaller inner bores, difficulties arise when trying tomaintain precision and accuracy throughout the length. This is alsochallenging with glass for example, where the internal channel is formedover a mandrel. In addition, small inner diameter bores requires smallseals. Both tip seals and compression seals are very difficult tomanufacture with precision, and due to their size they wear out andconsequently leak relatively quickly.

[0089] Due to the difficulty in manufacturing rugged seals, analternative approach is to eliminate the separate seals so that thesealing takes place between the hard material outer surface of theplunger or piston and the inner surface of the bore tubing directly. Inthe past, ultra precise and often custom-ground glass syringe plungerswere made to slide close inside glass tube bores so that glass provideda liquid tight or even air tight seal on glass. Ceramic pistons insideof ceramic bores have also been used successfully. However, this designleads to many limitations on materials of use, tends to be expensive,and the rigid materials are prone to jamming up if any solid getsinside. Therefore, it shows little promise of economical and practicalapplication value.

[0090] However, the present invention overcomes all of thesedifficulties because there is no need for smaller and smaller parts tometer smaller and smaller volumes when using the Differential Mode. Toreiterate, a traditional extremely fine resolution 10 microliter syringe(which is the standard 6 cm or 2.37 inches in length) has a tube innerdiameter bore of only 0.018 inches. This corresponds to the seal sizerequired, and is about the size of a needle. This may be too small forpractical automated applications but can be used in special researchapplications. The present invention, with its Differential Mode, cangive the same fine resolution equivalent to the above described 10microliter volume syringe by using a housing or tube with an innerdiameter of 0.181 inches (4.6 mm) in conjunction with a piston that hasan outer diameter of 0.180 inches. The relatively large size of thepresent invention is comparable to a traditional or standard 1milliliter (1000 microliter) syringe which is 100 times larger in volumethan the above mentioned 10 microliter volume syringe. The size of thepresent invention is much more practical to manufacture and incorporateinto an automated system, and it eliminates the sealing problemsassociated with using tiny seals.

[0091] Having thus described several aspects of at least one embodimentof this invention, it is to be appreciated various alterations,modifications, and improvements will readily occur to those skilled inthe art. Such alterations, modifications, and improvements are intendedto be part of this disclosure, and are intended to be within the spiritand scope of the invention. Accordingly, the foregoing description anddrawings are by way of example only, and the scope of the invention islimited by the appended claims and their equivalents.

What is claimed is: 1-54. (Canceled)
 55. A syringe comprising: a housingwith a chamber formed therein; a piston extending lengthwise within thechamber and movable relative thereto, the chamber defined by the innersurface of the housing and spaced portions of the outer surface of thepiston; and means extending from an end of the piston defining a passagefor fluid outwardly of the chamber.
 56. A syringe as set forth in claim55, wherein said means extending from an end comprises an extension ofsaid piston having an axially extending passage with one end of thepassage in fluid communication with the chamber and the other end of thepassage extending outwardly of the chamber.
 57. A syringe as set forthin claim 56, wherein said piston has a frusto-conic section forming atapered section and at least one resilient seal between the innersurface and a portion of the frusto-conic section.
 58. The syringe asset forth in claim 56, further comprising a sealing means fixed to theinner surface of the housing and movable relative to the piston, formingan end of the chamber.
 59. The syringe as set forth in claim 58, furthercomprising a second sealing means fixed to the extension of the pistonhaving an axially extending passage, forming an end of the chamber.60-65. (Canceled)
 66. A syringe comprising: a housing with an elongatedmember therein; a chamber defined at least in part by the inner surfaceof the housing and the outer surface of the member; wherein movement ofthe housing relative to the elongated member changes the volume of thechamber; and a passage extending from one end of the chamber for fluidflow into the chamber.
 67. The syringe of claim 66, wherein thecross-section of at least a portion of the chamber is annular in shape.68. The syringe of claim 66, wherein the cross-section of at least aportion of the member is circular in shape.
 69. The syringe of claim 66,further comprising a first sealing means positioned within the housing,defining a second end of the chamber.
 70. The syringe of claim 66,further comprising a notch in the member, defining a breakout hole forfluid communication between the chamber and the passage.
 71. The syringeof claim 70, wherein the passage is axially aligned with the housing.72. The syringe of claim 69, further comprising a second sealing meanspositioned within the housing, at one end of the chamber.
 73. Thesyringe of claim 66, wherein the passage is formed by an extension ofsaid elongated member having an axially extending opening therethrough.74. The syringe of claim 66, wherein the length of the chamber isgreater than the length of the member within the chamber, such that thechamber is defined at least in part by a segment not occupied by themember.
 75. A syringe comprising: a housing with a chamber formedtherein; a member extending at least partially within the housing, thechamber defined by the inner surface of the housing and spaced portionsof the outer surface of the member; means for varying the volume of thechamber; and means extending from one end of the chamber defining apassage for fluid flow into the chamber.
 76. The syringe of claim 75,wherein the means for varying the volume of the chamber includes themember slidably fit within the housing such that the housing movesrelative to the member.
 77. The syringe of claim 75, wherein the meansextending from one end of the chamber comprises a plunger having anaxially extending passage therethrough.
 78. The syringe of claim 77,further comprising a notch in the member, defining a breakout hole forfluid communication between the chamber and the passage.
 79. The syringeof claim 75, wherein the cross-section of at least a portion of thechamber is annular in shape.
 80. The syringe of claim 75, wherein thecross-section of at least a portion of the member is circular in shape.